J . Org. Chem. 1987,52, 1133-1136 ~~
Table IV. Coordinates for (Aza-12-crown-4h NaI atom X Y z X 0 0.79062 (1) I 0 X Na 0.43313 (8) 0.00259 (8) 0.6568 (2) 01 0.3036 (1) 0.03122 (10) 0.4104 (2) 0.1935 (2) 02 0.10192 (8) 0.3453 (2) 0.4148 (2) 03 0.07463 (9) 0.5933 (2) 0.5290 (2) N 0.0850 (1) 0.7095 (3) 0.4493 (3) c1 0.0280 (1) 0.7545 (2) 0.3864 (3) c2 0.6493 (3) 0.0291 (2) 0.1767 (3) c3 0.0121 (2) 0.5200 (4) 0.1170 (3) c4 0.0921 (2) 0.3779 (4) c5 0.1784 (3) 0.1093 (1) 0.2872 (3) C6 0.2882 (4) 0.1480 (1) 0.4345 (3) c7 0.4478 (4) 0.5182 (3) 0.1277 (1) 0.5618 (3) C8 ~
used. Refinement was carried out by full-matrix least squares based on F with weights w = b ( F a ) ,treating non-hydrogen atoms anisotropically. Hydrogen atoms were located by difference maps and refined isotropically. Convergence was obtained (A/ p maximum = 0.04) in P43212with agreement factors listed above. Seven
1133
reflections had A F greater than 5a(F), none greater than 7u(F). Refinement under identical conditions in P41212yielded R = 0.033, R, = 0.038, GOF = 1.926, 51 reflections with AF > 5a(F), and five reflections with AF > 8u(F). The difference in R, is significant at better than CY = 0.005 by the Hamilton R factor ratio test.27 Coordinates for the correct configuration are listed in Table IV.
Acknowledgment. We warmly thank t6e National Institutes of Health (G.W.G.), W. R. Grace & Co. (G.W.G.), and the Donors of the Petroleum Research Fund, administered by the American Chemical Society (R.L.G.) for support of this work. Supplementary Material Available: Anisotropic thermal parameters for (C&I17N0&NaI, coordinates and isotropic thermal parameters for hydrogen atoms of (CBH17N03)1"aI, projection of the structure along the c axis, and view of the unit cell slightly oblique to the b axis, with c vertical (4 pages). Ordering information is given on any current masthead page. (27) Hamilton, W. C. Acta Crystallogr. 1965, 18, 502.
Regioselective Functionalization of Pyridinesulfonic Acids. Ortho-Lithiation of Tertiary 2- and 4-Pyridinesulfonamides F. Marsais, A. Cronnier, F. Trecourt, and G. Queguiner* Laboratoire de Chimie Organique HBtBrocyclique de l'ZRCOF, Znstitut National des Sciences AppliquBes, BP 08, 76130 Mont Saint Aignan, France Received January 22, 1986
Tertiary 2- and 4-pyridinesulfonamides were ortho-lithiated at low temperature by an excess of lithium diisopropylamide. Proton abstraction occurs selectively at the more acid 3-positions in the two cases. 3-Lithio-2and -4-(piperidinosulfony1)pyridines reacted with such electrophiles as iodine, aldehydes, 3-pentanone, dimethylformamide, and carbon dioxide to give the corresponding ortho-disubstituted pyridines in high yields. Lithiation ability of the pyridinesulfonamides was also compared with that of the benzene analogue.
Electron-rich heteroaromatia such as pyrrole, furan, and thiophene easily undergo electrophilic substitution. However, this powerful synthetic tool can seldom be used with electron-deficient heteroaromatic compounds such as pyridine and quinoline. Metalation is another powerful and regioselective method for substituting aromatic derivatives,' but it has only recently been applied to pyridines2 because of the peculiar reactivity of the pyridine ring toward nucleophilic metdating agents such as chelated alkyllithiums. A proper choice of reaction conditions allows the directed lithiation of pyridines that bear orthodirecting groups.2 Little work has been done on the metalation of compounds bearing a sulfur-containing substituent except for our recent short report on the metalation of tertiary 3pyridine sulfonamide^.^ In the homoaromatic ~ e r i e sa, ~ (N,N-dialky1amino)sulfonylmoiety is an effective orthodirecting group for metalation of sulfonic acids. These lithiations are carried out with nucleophilic chelated al-
kyllithiums, which are ineffective with pyridine anal o g u e ~ . We ~ ~ ~report here on the metalation of 2- and 4-pyridinesulfonamides. Results 2-[ (NJV-Dialkylamino)sulfonyl]pyridinesla-c were prepared from commerical 2-pyridinethiol via 2pyridinesulfonyl chloride.6 4- [ (N,N-Dialky1amino)sulfonyl]pyridines 2a-c were obtained by a four-step sequence starting from commerical4-nitropyridine N-0xide.I Metalation of Pyridinesulfonamides. Lithiation of 2-pyridinesulfonamides la-c was performed at low temperature by using an excess of lithium diisopropylamide (LDA). The 3-lithio derivatives 3a-c were quenched with benzophenone at -70 OC to give 4a-c in yields of 87-95%. Under similar conditions, 4-pyridinesulfonamides 2a-c were substituted in the 3-position to give 6a-c. (5) Abramovitch,R. A.; Ahmed, K. S.; Giam,C . S. Can. J. Chem. 1963, 1752. (6) 2-Pyridinesulfonylchloride has been prepared by chlorination of 2-pyridinethiol? Overall yields of 2a-c are, respectively, 70%, 75%,and
41,
(1)For a general review of metalation, see: Wakefield, B. J. The Chemistry of Organolithium Compounds;Pergamon: Oxford, 1974. For a recent review of the scope of directed metalation, see: Gschwend, H. W.; Rodriguez, H. R. Org. React. (N.Y.)1979, 26, 1. (2) Marsais, F.; Queguiner, G. Tetrahedron 1983,39, 2009. (3) Breant, P.; Marsais, F.; Queguiner, G.Synthesis 1983, 822. (4) Watanabe, H.; Schwartz,R. A.; Hauser, C. R.; Slocum,D. W. Can. J . Chem. 1965,47, 1543.
80%.
(7) Ochiai, E. J . Org. Chem. 1953,18,538. Angulo, J.; Municio, A. M. An. R. SOC.Esp. Fis. Quim.,Ser. B. 1960,56,395. The overall sequence is as follows: 4-chloropyridine N-oxide, 4-pyridinethiol N-oxide, 4pyridinesulfonyl chloride N-oxide, and 4-[ (NJ-dialkylamino)sulfonyl]pyridine N-oxides. Overall yields of la-c have been optimized to 50%, 35%, and 60%, respectively.
0022-3263 18711952-1133$01.50/0 , . 0 1987 American Chemical Society I
,
1134 J . Org. Chem., Vol. 52, No. 6,1987
Marsais et al.
T h e best yield (95%) of purified 4a was obtained from 2-(piperidinosulfony1)pyridine (la) by using 2 equiv of
with manganese dioxide in refluxing toluene.8
n
LDA in diethyl ether a t -70 "C for 1.5 h.
-R
a, R2
-
(CHZ)>
b , Rz = ICtizCti2)I0
c , Rz
LDA/Et20/
1
- 70-C
,
11
?h2CO/
-
7O'C
(CHZ)~
Lithiation of 4-(piperidinosulfonyl)pyridine(2a) proved t o be highly sensitive t o t h e amount of LDA a n d t o t h e reaction time. It appears t h a t reaction of 5a with benzaldehyde or iodine produced small amounts of t h e corresponding 3,5-disubstituted sulfonamides 21 and 22 in addition to t h e 3-monosubstituted 14 a n d 16.
PhHOHC
22
!4
i. B
C(C++)zOH
k
2
CH0HC6Hj
.@
CHOHC6H3C12-2,4
%".
-A?
CH3
2@
30
v,
The 'H NMR spectra were obtained by using a Varian A 60 spectrometer and are recorded in ppm downfield of the internal standard of Me4& (CDCl,) or HMDS (Me2SO-d6).lH-'H coupling constants are in good agreement with the common values: 5 2 - 3 N 5 Hz; 53-4 N 8 Hz; 52-4 N 2 Hz. IR spectra were obtained as potassium bromide dispersions from a Perkin-Elmer R-12 spectrometer. Wavenumbers are given for main absorptions (OH, C=O, C=C and C=N, S02-N. Elemental analyses were performed on a CHN Carlo Erba instrument. Diethyl ether (Ego) and tetrahydrofuran (THF) were distilled from benzophenone/sodiumand stored over 3-A molecular sieves. The water content of the solvents was estimated by the modified Karl-Fischer method:l0 Et20 < 10 ppm, THF < 45 ppm. Diisopropylamine, piperidine, morpholine, and pyrrolidine were redistilled from and stored over CaH2. Metalations were performed under a dry deoxygenated-argon atmosphere. The n-butyllithium (BuLi) content of the commercial hexane solution was estimated by the Gilman double titration method. All compounds had 'H NMR peaks in the vicinity of 1.60 (CH2) and 3.30 (CH2N). Satisfactory analyses (C, H, N) were obtained for all compounds. Synthesis of 2- and 44(Dialkylamino)sulfonyl]pyridines. 4-[ (Dialkylamino)sulfonyl]pyridineN-oxides were prepared by bubbling C12 into a cold (-5 "C) solution of 4-mercaptopyridine N-oxide7 (10 g, 0.08 mol) in 130 mL of 9 N HC1. The solution was neutralized by addition of CaC03 (10 g) at -5 "C, then of CHCl:, (200 mL) and fiially of CaC0, at -10 "C. The supernatant liquid was separated, and the remaining paste was washed twice with cold CHC1, (50 mL). The combined extracts were dried over MgS04 at 0 "C. The cold filtered solution was slowly aded at 0 "C to a mixture of the secondary amine (2 equiv, 0.16 mol) and CHC1, (100 mL). Stirring was continued for 1 h at 0 O C and 2 h at room temperature before washing with water (2 X 50 mL). Drying over MgS04and solvent removal gave a solid, which was purified by crystallization from Et20. The 4-[(dialkylaminolsulfonyllpyridine N-oxides were reduced with hydrogen in CH30H
18
%m
11
-
CHOHCH3
12
CHO
w
13
COZH
8.
Iji"
a
22
Experimental Section
Metalation of 2a with 3 equiv of LDA a n d reaction of benzaldehyde (3 equiv) for 3 h a t -70 OC led t o 32% of the 3,5-disubstituted product 22. Under t h e same conditions, 2 equiv of LDA gave only 20% of 22. T h e best monometalation selectivity was otained by using a twofold excess of LDA a n d reacting t h e electrophile a t -70 " C for a half-hour. Deuteriolysis experiments excluded a 3,5-dilithio derivative, a n d one must suppose t h a t 3-monosubstituted sulfonamides 14 and 16 were further lithiated by excess of LDA. This is d u e t o t h e low reactivity of LDA toward iodine or benzaldehyde. Analogous 3,5-disubstituted derivatives were not isolated from reaction of 5a with other electrophiles, a n d no disubstituted products were observed in reactions of 3a. Lithiated species 3a-c and 5a-c were white precipitates t h a t were quite stable a t low temperature. Both lithiated compounds 3a and 5a reacted a t -70 "C with such electrophiles as iodine, 3-pentanone, benzaldehyde, 2,4-dichlorobenzaldehyde, acetaldehyde, dimethylformamide, and carbon dioxide to give 3-substituted compounds 7-13 a n d 14-20, respectively, in yields of 5595%.
a
&
C6H3C12-2,4
49 v
I
'sH5
"C.
29
21
Z?
a
We also compared the lithiation ability of a tertiary benzenesulfonamide with t h a t of t h e pyridine analogues. (Piperidinosulfony1)benzene (29)9reacted with 2 equiv of LDA in diethyl ether a t -75 "C.Addition of benzophenone gave only a 5% yield of diphenyl[ (piperidinosulfony1)phenyllmethanol (30). A higher lithiation yield was obtained by increasing the metalation temperature: 55% of tertiary alcohol 30 could be isolated after lithiation a t 0
w
^sr
w
19
Secondary alcohols 9-11 and 16-18 were easily oxidized t o t h e corresponding ketones 23-28 in quantitative yields
(8) Attenburow, J.; Cameron, A. F. B.; Chapman, J. H.; Evans, R. M.; Hems, B. A,; Jansen, A. B. A.; Walker, T. J. Chem. SOC.1952, 1094. (9) Buchi, J.; Aebi, A,; Kuhn, Th.; Eichenberger, E. Helu. Chim. Acta 1956, 189, 1579. (10) Bizot, J. Bull. SOC.Chim. Fr. 1967, I , 151.
J . Org. Chem., Vol. 52, No. 6, 1987 1135
Tertiary Pyridinesulfonamides with h e y Ni catalyst (0.08 mol of N-oxide in 150 mL of CH30H and 40 g of Ni). The reactions were carried out a t slightly over 1 atm and required about 5 h. Filtration over Celite and evaporation of CH30H gave quantitative yields of pure white solid. 2-[(Dialkylamino)sulfonyl]pyridineswere prepared by the same procedure with commerical2-mercaptopyridine as starting material. 2-(Piperidinosulfonyl)pyridine(la): yield 70%; mp 59 "C; 'H NMR (CDCl,) 6 1.60 (m, 6 H, CHJ, 3.85 (m, 4 H, CHzN),7.50 (m, 1H, H5),7.90 (m, 2 H, H, + H4),8.70 (dd, 1 H, He); IR 3090, 3050,3000,2980,2960,2940,2920,2850,2845,1575,1560,1465,
1450, 1435, 1425 cm-'. Anal. Calcd for C10H14N202S:C, 53.08; H, 6.24; N, 12.38. Found: C, 53.1; H, 6.19; N, 12.3. 4-(Piperidinosulfonyl)pyridine(2a): yield 75%; mp 122 "C; 'H NMR (CDCl,) 6 1.55 (m, 6 H, CH,), 3.00 (m, 4 H, CH,N), 7.55 (d, 2 H, H3 + H5), 8.85 (d, 2 H, Hz + He); IR 3100, 3060, 3040, 2960, 2880, 1570, 1550, 1460, 1450, 1400 cm-'. Anal. Calcd for C1,,H14N20&3:C, 53.08; H, 6.24; N, 12.38. Found C, 53.0; H, 6.09, N, 12.2. Lithiation of 2- and 44(Dialky~amino)sulfonyl]pyridines and Reactions with Electrophiles. n-Butyllithium (1.6 M in hexane, 15.5 mL, 0.025 mol) was slowly added to a solution of diisopropylamine (2.53 g, 0.025 mol) in EtsO (50 mL) at -30 "C under argon. Stirriig was continued for 1h at 0 "C. The resulting mixture was cooled at -70 "C, and 2-[(dialkylamino)sulfonyl]pyridine (0.0125 mol) in THF (30 mL) was added dropwise. After the mixture was allowed to stand at -70 "C for 1.5 h, a solution of the electrophile (0.025 mol) in THF (30 mL) was added. The mixture was allowed to stand for 3 h at -70 "C before hydrolysis at -70 "C (H,O/THF, 1 mL/10 mL) and addition of water (100 mL) at room temperature. After extraction of the aqueous layer with CHC13 (2 X 100 mL), the combined organic extracts were dried over MgSO, and concentrated under vacuum before purification (the reaction with benzaldehyde or iodine at -70 "C required only 0.5 h, starting from 4-pyridinesulfonamide 2a). Diphenyl[2-(piperidinosulfonyl)-3-pyridyl]methanol(4a): from la and benzophenone; recrystallized from Et,O; yield 95%; mp 182 OC; 'H NMR (CDCl,), 6 6.75 (s, 1 H, OH), 7.25 (m, 12 H, C6H5 H5 + H4),8.55 (m, 1H, He);IR 3360,1600,1570,1550, 1490, 1465, 1450, 1440, 1430, 1375, 1160 cm-'. Anal. Calcd for C23H24N203S: C, 67.62; H, 5.92; N, 6.86. Found C, 67.4; H, 5.91; N, 6.78. 3-Deuterio-2-(piperidinosulfonyl)pyridine: from la and CH30D. Recrystallization from EhO yields a mixture of la (15%) and the 3-deuterio derivative (85%); mp 59 "C; 'H NMR (CDC1,) 6 7.55 (m, 1 H, H5),7.95 (m, 1.15 H, H, H4),8.70 (dd, 1 H, He). Phenyl[2-(piperidinosulfonyl)-3-pyridyl]methanol (9): from la and benzaldehyde; recrystallized from Ego; yield 90%; mp 106 "C; 'H NMR (CDCl,) 6 3.85 (s, 1 H, OH), 6.75 (s, 1 H, CH), 7.35 (m, 6 H, C6H5 H5), 7.75 (dd, 1 H, H4),8.45 (dd, 1H, He); IR 3490,1605,1580,1565,1500,1470,1450,1420,1435,1335, 1170 cm-'. Anal. Calcd for C17H20N203S:C, 61.42;, H, 6.06; N, 8.43. Found: C, 61.3; H, 6.06; N, 8.38. 3-Formyl-2-(piperidinosulfonyl)pyridine(12): from la and dimethylformamide as for 19; yield 55%; mp 79 "C; 'H NMR (CDCl3) 6 7.60 (dd, 1 H, H5), 8.35 (d, 1H, H4), 8.75 (d, 1 H, He), 10.90 (s, 1H, CHO); IR 1700,1680,1575,1475,1460,1440,1430, 1340, 1175 cm-'. Anal. Calcd for CllH14N203SC, 51.93; H, 5.55; N, 11.02. Found: C, 51.8; H, 5.66; N, 10.5. 3-Iodo-2-(piperidinosulfonyl)pyridine (7): from la and iodine; decolorized with NaHS03,decanted, extracted with CHCl,, dried over MgSO,, and concentrated under vacuum; yield 90% ; mp 145 OC; 'H NMR (CDCl,) 6 7.10 (dd, 1H, H5),8.35 (dd, 1 H, H4), 8.50 (dd, 1H, He); IR 1575,1555,1470,1455,1445,1435,1420, 1400, 1345, 1170 cm-'. Anal. Calcd for CloH231NzOzS:C, 34.10; H, 3.72; N, 7.95. Found: C, 33.5; H, 3.55; N, 7.38. 2-(Piperidinosulfonyl)pyridine-3-carboxylic Acid (13). Lithiated la was quenched with dry ice (50 9). The product was hydrolyzed at 0 OC with HzO (150 mL) and extracted with CHCl, (2 x 50 mL). The aqueous solution was acidified to pH 2 and extracted with CHC13 (2 X 50 mL). The organic extracts were dried (MgS04)and evaporated, and the residue was dried under vacuum: yield 85%; pasty melt at 150 "C; lH NMR (CDCI,), 6 7.60 (dd, 1 H, H5), 8.00 (dd, 1 H, H4), 8.65 (dd, 1 H, He), 9.85 (s, 1 H, COZH); IR 3190,1750,1580,1560,1470,1460, 1450, 1440, 1415 cm-'. Anal. Calcd for CllH14N204S:C, 48.88; H, 5.22; N,
+
+
+
10.36. Found C, 48.5; H, 5.34; N, 10.2.
Diphenyl[4-(piperidinosulfonyl)-3-pyridyl]methanol (6a): from 2a and benzophenone; purified by steam distillation and recrystallization from Et,O; yield 95%; mp 135 "C; 'H NMR (CDCls) 6 6.55 (8, 1 H, OH), 7.30 (9, 10 H, Ph), 7.65 (d, 1 H, H5), 8.10 (8, 1H, HA, 8.65 (d, 1H, H&;IR 3480,3420,1600,1585,1565, 1535, 1495, 1465, 1450, 1400, 1335, 1170 cm-'. Anal. Calcd for CBH,Nz03S: C, 67.62;, H, 5.92; N, 6.86. Found: C, 67.6; H, 6.06; N, 6.86. 3-Deuterio-4-(piperidinosulfonyl)pyridine:from 2a and CH30D. Recrystallization from EtzO yields quantitatively the 3-deuterio derivative;mp 122 OC; 'H NMR (CDC13)6 7.55 (d, 1.02 H, Hs + H3), 8.85 (m, 2 H, Hz + He). Phenyl[4-(piperidinosulfonyl)-3-pyridyl]methanol (16): from 2a and benzaldehyde; purified by steam distillation, drying, and flash chromatography over silica gel (Et,O); yield 88%; mp 79 "C; 'H NMR (MezSO)6 4.90 (s, 1 H, OH), 6.75 (s, 1 H, CH), 7.25 ( 8 , 5 H, Ph), 7.60 (d, 1 H, H5), 8.50 (d, 1 H, Hs), 8.80 (s, 1 H, Hz);IR 3500, 1570,1500,1460,1455,1450,1420,1335,1170 cm-'. Anal. Calcd for Cl7HZ0N2O3S:C, 61.42; H, 6.06; N, 8.43. Found: C, 61.2; H, 5.96; N, 8.22. [5-(Hydroxyphenylmethyl)-4-(piperidinosulfonyl)-3pyridyllphenylmethanol (22): from 2a and benzaldehyde; steam distillation, drying, and separation from 16 by flash chromatography over silica gel (Et20);yield 9%; mp 117 "C; 'H NMR (Me2SO)6 4.50 (5, 1 H, OH), 6.75 (s, 1 H, CH), 7.25 (s, 5 H, Ph), 8.85 (s, 2 H, Hz + H6); IR 3500, 1600, 1580, 1495, 1470, 1450,1440,1420,1340,1160cm-'. Anal. Calcd for C24H26N204S: C, 65.71; H, 5.98; N, 6.39. Found: C, 65.8; H, 5.90; N, 6.27. 3-Iodo-4-(piperidinosulfonyl)pyridine (14): from 2a and iodine as for 7; separated from 21 by crystallization from EtzO/hexane; yield 86%; mp 97 "C; 'H NMR (CDCl,) 6 7.95 (d, 1H, H5), 8.80 (d, 1H, He), 9.25 (s,1H, Hz); IR 1555, 1465, 1455, 1445, 1335, 1170, 1060 cm-'. Anal. Calcd for CloH131N202S:C, 34.10; H, 3.72; N, 7.95. Found: C, 34.0; H, 3.78; N, 8.05. 3,5-Diiodo-4-(piperidinosulfonyl)pyridine(21): from 2a and iodine; separated from 14 by crystallization from EtzO/ hexane; yield 7%; mp 133 "C; 'H NMR (CDCl,) 6 9.20 (s, 2 H, Hz + He); IR 1620,1550,1480,1460,1440,1420,1340,1180,1150 cm-'. Anal. Calcd for Cl,,H121zNzOzS:C, 25.10; H, 2.53; N, 5.86. Found: C, 25.2; H, 2.54; N, 6.01. 3-Formyl-4-(piperidinosulfonyl)pyridine(19): from 2a and dimethylformamide (2.5 equiv) at -40 "C for 1h; decanted, extracted (CHCI,), dried over MgSO,, concentrated under vacuum, and recrystallized (Et,O/hexane, l / l ) ; yield 90%; mp 90 "C; 'H NMR (CDC13) 6 7.75 (d, 1 H, H5), 9.05 (d, 1H, He), 9.30 (s, 1 H, Hz), 11.20 (s,1 H, CHO); IR 1690, 1560, 1465, 1445, 1045, 1340, 1180 cm-'. Anal. Calcd for CllH14N203S:C, 51.93; H, 5.55; N, 11.12. Found: C, 52.0; H, 5.52; N, 10.9. 4-(Piperidinosulfonyl)pyridine-3-carboxylic acid (20): from la as for 13; yield 75%; pasty melt at 140 "C; 'H NMR (Me2SO)6 7.65 (d, 1 H, H5),8.70 (s, 1 H, H,), 8.75 (d, 1 H, He); IR 3420,1730, 1585, 1575, 1470, 1450, 1400 cm-'. Anal. Calcd for CllH14N204S:C, 48.88; H, 5.22; N, 10.36. Found: C, 48.5; H, 5.34; N, 9.84. 2- a n d 4-[(Dialkylamino)sulfonyl]-3-pyridylKetones. Alcohols 9-11 and 16-18 (5 mmol) were oxidized with MnO, (50 mmol) in dry toluene (200 mL) at reflux in a Dean-Stark apparatus, with the reaction monitored by TLC on silica gel (EtzO). The mixture was filtered on Celite, dried (MgSO,), and evaporated under vacuum to give quantitative yields of ketones. Phenyl[2-(piperidinosulfonyl)-3-pyridyl]methanone(23): from 9, purified by flash chromatography over silica gel (Et20/hexane,40/60); mp 104 "C; 'H NMR (CDCl,) 6 7.80 (m, 7 H, H4 + H5 + CsH5), 8.75 (dd, 1 H, He); IR 1680,1600,1585, 1555, 1470, 1455, 1405, 1345, 1175 cm-'. Anal. Calcd for C10H18NZ03S: C, 61.80; H,5.49; N, 8.48. Found: C, 61.9; H,5.39; N, 8.46. Phenyl[ 4-(piperidinosulfonyl)-3-pyridyl]methanone(26): from 16, purified by crystallization from EhO; mp 90 "C; 'H NMR (CDC13)6 7.15 (m, 6 H, H5 C6H5),8.55 (s, 1 H, H,), 8.80 (d, 1 H, He); IR 1680,1600,1585,1570,1470,1455,1400,1350,1170 cm-'. Anal. Calcd for C17H18N203S:C, 61.80; H, 5.49; N, 8.48. Found: C, 62.92; H, 5.34; N, 8.19. (Piperidinosulfony1)benzene(29)? Benzenesulfonyl chloride (10 g, 0.057 mol) was slowly added at room temperature to a
+
J. Org. C h e m .
1136
solution of piperidine (9.7 g, 0.114 mol) in dry toluene (50 mL). The mixture was stirred for 3 h and washed with water (3 X 50 mL). Drying over MgS04, evaporation of the solvent, and crystallizationof the residue from EGO afforded 29 in 85% yield; mp 91 "C; 'H NMR (CDC1,) 6 7.55 (m, 5 H, C6H5);IR 1630,1485, 1470, 1450, 1340, 1180 cm-'. Anal. Calcd for CllH15N02S: C, 58.64; H, 6.71; N, 6.22. Found: C, 58.8; H, 6.85; N, 6.25. Diphenyl[2-(piperidinosulfonyl)phenyl]methanol (30). Lithiation of 29 with LDA was carried out at 0 "C followed by reaction with benzophenone at -70 "C. Unreacted starting materials were removed by steam distillation. Flash chromatography of the dried product over silica gel (EtO/hexane, 15/75) yielded 30 (55%);mp 160 "C; 'H NMR (CDCl,) 6 6.85 (s, 1 H, OH), 7.25 (m, 12 H, CsH5+ H4 H5), 7.90 (m, 1 H, HJ; IR 3370,1595,1580, 1540, 1490, 1445, 1430, 1405, 1330, 1145 cm-I. Anal. Calcd for C24H25N03S:C, 70.71; H, 6.19; N, 3.44. Found: C, 70.7; H, 6.31; N, 3.36.
+
Registry No. la, 106762-43-0;lb, 106762-44-1; IC,106762-45-2; 2a, 715-07-1;2b, 715-08-2; 2c, 106762-42-9;4a, 106762-58-7; 4b,
1987, 52, 1136-1139 106762-59-8; 4c, 106762-60-1; 5,33486-07-6; 6a, 106762-46-3; 6b, 106762-47-4; 6c, 106762-48-5; 7, 106762-66-7; 8, 106762-61-2; 9, 106762-62-3; LO, 106762-63-4; 11, 106762-64-5; 12, 106762-65-6; 13,106762-67-8; 14,106762-51-0; 15,106762-53-2; 16,106762-49-6; 17, 106762-54-3; 18,106762-55-4; 19,106762-56-5; 20,106762-57-6; 21,106762-52-1; 22,106762-50-9; 23,106762-69-0; 24,106762-70-3; 25,106762-68-9; 26, 106762-72-5;27,106762-73-6; 28,106762-71-4; 29, 5033-23-8; 30, 106762-74-7; C~H,OC~H5,119-61-9; C6H&HO, 100-52-7; Iz, 7553-56-2; CzHsCOCzH5,96-22-0;2,4-Cl&H&HO, 874-42-0; H3CCH0, 75-07-0; (CH3)2NCHO,6812-2; COZ, 124-38-9; C6H,SO&l, 98-09-9; piperidine, 110-89-4; morpholine, 110-91-8; pyrrolidine, 123-75-1; 4-(piperidinosulfony1)pyridine oxide, 71909-5; 4- (morpholinosulfony1)pyridine oxide, 884-96-8; 4-(pyrro1idinosulfonyl)pyridine oxide, 106762-41-8; 2-pyridinethione, 2637-34-5. Supplementary Material Available: Experimental procedures and complete 'H NMR and IR spectral data for compounds 1, 2, 4, and 6-30 (16 pages). Ordering information is given on any current masthead page.
Notes trimethylsilane and styrene. The resulting products are formal iris + 7r2, cycloadducts derived from an inverseelectron-demand Diels-Alder reaction and are formed both regio- and stereoselectivity,reflecting endo addition of the dienophile to the electron-deficient iminium diene system. George D. Hartman,* Brian T . Phillips, and Wasyl Halczenko Formal irq,+ 7%cycloaddition reactions between dienophiles and 2-aza dienes have been extensively ~tudied.~,' Merck Sharp & Dohme Research Laboratories, West Point, This work has shown that both normal- and inversePennsylvania 19486 electron-demand Diels-Alder type reactions depend upon the electronic nature of substituents on the aza diene. In James P. Springer and Jordan Hirshfield the case of inverse-electron-demand processes, the utilization of Lewis acid catalysis to render the diene more Merck Sharp & Dohme Research Laboratories, Rahway, electron deficient has resulted in successful cyclization N e w Jersey 07065 under mild conditions.g12 Received July 18, 1986 Unlike the examples described above that relate to reaction of a 2-aza diene in which the nitrogen is either neutral or formally charged by virtue of complexation1' We have recently reported the generation of iminium with a Lewis acid, our published results'" have described ions from 4-aryl-1,4-dihydropyridines and the intramo2-aza diene systems that are positively charged from colecular trapping of these electrophilic intermediates with valent binding of nitrogen to a proton or alkyl group. In carbon-carbon double bonds' and reactive heterocycle^.^,^ this respect our work is perhaps more closely aligned We have also noted other cyclization modes for 1,4-dimechanistically with that of Bradsher and co-workers,13 hydropyridines that either compete with iminium ion who have demonstrated facile cationic polar cycloaddition formation4 or utilize the iminium species at a secondary between acridizinium salts and vinyl ethers, and that of stage in the cy~lization.~We now report that the iminium ion derived from dimethyl 2,6-dimethyl-4-phenyl-l,4-di- Stevens et al.14 and Franck et al.15 It was therefore the hydropyridine-3,5-dicarboxylate(1; Scheme I) can be generated under conditions of Lewis acid catalysis and (6) For an excellent review, see Boger, D. L. Tetrahedron 1983, 39, efficiently trapped in an intermolecular sense by allyl28fi9. Iminium Ion Mediated Cyclizations of 4-Aryl-1,4-dihydropyridines.Regio- and Stereoselectivity i n Intermolecular Reactions
(1) The following library of crystallographic programs was used: MULTAN 80 [P. Main et al. University of York, York, England, 19801; ORTEP-II [C. K. Johnson, Oak Ridge National Laboratory, Oak Ridge, TN,
19701; SDP Plus V1.1 [Y. Okaya et al.,B. A. Frenz and Associates, College Station, TX, 19841. Hartman, G. D.; Halczenko, W.; Phillips, B. T. J. Org. Chem. 1985,50, 2427. (2) Hartman, G. D.; Halczenko, W.; Phillips, B. T.J . Org. Chem. 1986, 51, 142. (3) Hartman, G. D.; Halczenko, W.; Phillips, B. T.; Pitzenberger, S. M.; Springer, J. P.; Hirshfield, J. J. Org. Chem. 1986, 51, 2202. (4) Hartman, G. D.; Halczenko, W.; Cochran, D. W. Can. J . Chem. 1986, 64, 556. Halczenko, W. J . Org. Chem. 1985, (5) Hartman, G. D.; Phillips, B. T.; 50, 2423.
0022-3263/87/1952-ll36$01.50/0
(7) Demoulin, A.; Gorrisen, H.; Hesbain-Frisque, A.-M.;Ghosez, L. J. Am. Chem. SOC.1975,97, 4409. (8) Jung, M. A.; Shapiro, J. J. J. Am. Chem. SOC.1980, 102, 7862. (9) Povarvo, L. S.; Mikhailov, B. M. Izu. Akad. Nuuk SSSR, Ser. Khim. 1964, 2221. (10) Trifonov, L. S.; Orahovats, A. S. Heterocycles 1984, 22, 355. (11) Chenn. Y.-S.:Ha. E.: Mariano. P. S.: Amman, H. L. J. Or#. Chem. 1985,50, 567%. (12) Komatsu, M.; Takamatsu, S.; Uesaka, M.; Yamamono, S.; Ohshio, Y.; Agawa, T. J. Org. Chem. 1984, 49, 2691. (13) (a) Bradsher, C. K. Adu. Heterocycl. Chem. 1974, 16, 289. (b) Bradsher, C. K.; Carlson, G. L. B. Porter, N. A.; Westerman, I. J.; Wallis, T.G. J . Org. Chem. 1978,43, 822. (14) Stevens, R. V.; Pruitt, J. P. J. Chem. Soc., Chem. Commun. 1983, 1425. (15) Franck, R. W.; Gupta, R. B. Tetrahedron Lett. 1985, 293.
0 1987 American Chemical Society
